DESCRIPTION: (Applicant's Abstract) We and others have established that THC, the major psychoactive cannabinoid in marijuana, modulates the functions of immune cells in vitro and in vivo. However, suppression by cannabinoids of host immunity to infection has not been aggressively and thoroughly tested and is therefore still open to question. From our recent results, we have developed the hypothesis that cannabinoids depress immunity to infection by acting through cannabinoid receptors (CBR) and causing an imbalance in the immune cytokine network leading to a functional depression in cell-mediated immunity (CMI). The following aims are designed to test this hypothesis. Aim 1 will determine the extent of cytokine modulation and CMI suppression occurring following drug treatment. For these studies, mice will be injected with THC and infected with Legionella pneumophila and the tissue production of IL-4, IL-10, IL-12, IL-2, IFNy, IL-1, TNF, and IL-6 will be determined. In addition, the effect of drug treatment on number and function of CD8+cells which are CMI effector cells will be determined. Aim 2 will determine the role of CBRs in suppression of CMI. In these studies, structure/activity experiments will be done using various cannabinoid agonists such as THC, cannabinol, cannabidiol, CP55,940, WIN55,212-2, JWH-051, and JWH-015 as well as CB1 and 2 antagonists in order to test the drug effect on cytokine production and mortality from infection. In addition, we will determine the CB1 and CB2 phenotype of immune cell subpopulations by RT-PCR and protein detection. Aim 3 will determine the cellular immunology of the cannabinoid suppression of CMI. In these studies, cannabinoid effects on number and function of Th2 cells and other immune cells will be determined as well as the role of IL-4 and IL-12 in the drug effect on CMI suppression. Aim 4 will determine molecular aspects of the drug effect on cytokine production. In these studies, cannabinoid effects on the levels of cytokine-associated transcription factors, NFAT, AP-1, and NFkB, as well as the coupling of Gi and cAMP to the drug-induced modulation of cytokine production will be established. We propose these studies will establish that cannabinoids suppress immunity to infection by depressing CMI and the cytokine network and that the drugs are causing these changes by targeting cytokine production in certain immune cell subtypes by mechanisms involving CBRs. These results will address the safety issue of marijuana products as human medicines and increase our understanding of the role the cannabinoid system plays in immunity and host defenses to infection.